Nitric Oxide Synthase (NOS) in endothelial cells converts L-arginine to L-hydroxyarginine and subsequently to nitric oxide (NO) and L-citrulline (FIG. 1 and FIG. 2). NO exerts its biological action on smooth muscle by increasing cGMP, which leads to vasodialation and increased blood flow in the brain. Two L-citrulline molecules combine to generate L-arginine to boost the NO generation cycle. NO acts as a neurotransmitter for the autonomic nervous system, increases cerebral blood flow and oxygenation of the brain, and improves cognitive functions.
A previous dietary supplement was designed and sold to maximize the benefits of NO. It contained the amino acids L-citruline and L-arginine, as well as BioPerine® (extract, FIG. 3) that helps the body absorb the amino acids (see U.S. Pat. No. 5,536,506 and European Patent EP0810868B1). BioPerine® (extract) inhibits human CYP3A4 and P-glycoprotein enzymes. By inhibiting certain enzymes BioPerine® (extract) may alter the effectiveness of certain medications by increasing bioavailability. The active ingredients in this previous dietary supplement were the amino acids L-citruline and L-arginine, which served as a substrate for NO generation. The previous dietary supplement was sold and administered as a capsule containing 500 mg of L-citrulline, 250 mg of L-arginine, and 1.5 mg of bioperine. The recommended dosage was two capsules per day. In spite of the success realized with the previous dietary supplement, there remains a need for additional formulations that provide improved effects.